In the intricate and multifaceted ecosystem of a tumor, cancer-associated fibroblasts (CAFs) have emerged as key architects of the tumor microenvironment, orchestrating processes that promote cancer progression and immune evasion. Despite their critical cancer-supportive role, effective therapies that selectively target CAFs remain elusive. A groundbreaking study published in Nature in 2025 by Heide et al. sheds new light on this challenge, revealing a central molecular regulator within CAFs—nicotinamide N-methyltransferase (NNMT)—that reprograms the tumor stroma to suppress antitumor immunity. This discovery not only deepens our understanding of tumor biology but also unveils actionable avenues for therapeutic intervention.
NNMT, an enzyme known for its role in methylating nicotinamide, has now been implicated in driving profound epigenetic alterations within CAFs in high-grade serous ovarian cancer. Through a combination of sophisticated spatial transcriptomics and single-cell RNA sequencing, Heide and colleagues were able to map the precise cellular distribution and molecular signatures of CAFs in human tumors. Their analyses revealed that NNMT expression in CAFs leads to a hypomethylated state of the histone mark H3K27me3, a modification traditionally associated with gene repression. This epigenetic remodeling unlocks the transcription of genes responsible for the secretion of complement proteins—components of the innate immune system with unexpected roles in tumor immunity.
The secreted complement factors from NNMT-driven CAFs orchestrate a suppressive immune milieu by recruiting myeloid-derived suppressor cells (MDSCs) to the tumor site. MDSCs are notorious for their capacity to inhibit cytotoxic lymphocyte functions, effectively blunting the immune system’s capacity to recognize and destroy cancer cells. This CAF-mediated recruitment of MDSCs establishes a protective niche for tumor cells, promoting immune escape and fostering tumor growth. Fascinatingly, this mechanism appears to be a conserved pathway across multiple tumor types, underscoring the universal relevance of NNMT in the tumor microenvironment.
To probe the functional consequences of NNMT activity in CAFs, the researchers engineered Nnmt knockout mice and implanted syngeneic tumor models of ovarian, breast, and colon cancers. These immunocompetent mice exhibited significantly impaired tumor growth, attesting to the critical role of NNMT in sustaining tumor progression. The underlying driver of this impaired growth was a striking enhancement of CD8+ T cell activation, a key immune effector population responsible for killing tumor cells. This observation highlights the disruptive potential of targeting CAF-driven immunosuppression through NNMT ablation.
Recognizing the therapeutic promise of NNMT inhibition, Heide et al. embarked on an ambitious drug discovery campaign, deploying high-throughput screening to identify potent and selective NNMT inhibitors. Their most promising candidate demonstrated robust efficacy in multiple preclinical cancer models, attenuating both primary tumor burden and metastatic dissemination. Importantly, NNMT inhibition re-sensitized tumors to immune checkpoint blockade therapies, which had previously failed due to a suppressive microenvironment dominated by CAFs and MDSCs. This synergy between NNMT inhibitors and immunotherapy suggests a new combinatorial approach that could overcome existing forms of therapeutic resistance.
The molecular cascade initiated by NNMT in CAFs effectively links metabolism, epigenetics, and immune modulation within the tumor microenvironment. NNMT consumes cellular methyl groups through nicotinamide methylation, leading to a global reduction in methyl donors available for histone modification. The resulting H3K27me3 hypomethylation alleviates transcriptional repression of complement genes, which would otherwise remain silenced. This metabolic-epigenetic reprogramming exemplifies how cancer cells and their stromal neighbors manipulate fundamental biochemical pathways to hijack immune surveillance mechanisms.
Spatially resolved transcriptomic data further illuminated how this NNMT-driven mechanism manifests within the heterogeneous tumor landscape. CAFs with heightened NNMT expression localized to tumor stromal regions rich in immune suppressive myeloid populations, corroborating the biochemical findings. Single-cell RNA sequencing enabled the dissection of diverse CAF subpopulations, revealing that NNMT marks a protumorigenic subset particularly adept at sculpting an immunosuppressive niche. Such fine-grained insights are pivotal for the design of precision therapies targeting stromal cell subsets without collateral damage to normal tissue.
The translational potential of NNMT inhibition extends beyond ovarian cancer into breast and colon cancers, as demonstrated by the usage of syngeneic mouse tumor models. This cross-cancer applicability underscores the conserved nature of NNMT’s function in modulating tumor immunity, positioning NNMT inhibitors as broad-spectrum agents capable of rewriting the tumor microenvironment. Given the dire need for new therapeutic strategies against refractory and metastatic cancers, the discovery of NNMT as a linchpin in CAF-mediated immunosuppression is especially timely.
Moreover, the study elucidates the crucial interplay between CAFs and immune checkpoint blockade efficacy. Immune checkpoint inhibitors have revolutionized oncology, yet many patients fail to respond, largely due to stromal and myeloid factors that dampen T cell responses. By targeting NNMT, the team effectively dismantled this stromal barrier, unleashing robust CD8+ T cell-mediated cytotoxicity upon immunotherapy administration. This raises the possibility of combining NNMT inhibitors with existing immunotherapies to significantly amplify clinical responses and durability.
Beyond its immediate therapeutic implications, the Heide et al. study opens new avenues for understanding stromal cell biology and immunometabolism in cancer. The identification of a metabolic enzyme as a master regulator of CAF function challenges prior assumptions and emphasizes the need to consider metabolic-epigenetic crosstalk in the tumor microenvironment. Future research inspired by these findings may unravel additional metabolic nodes governing immune suppression or activation, offering further targets for cancer intervention.
Ultimately, this research elevates NNMT from a relatively obscure metabolic enzyme to a high-value target within the evolving landscape of cancer therapeutics. The convergence of multi-omics analyses, robust genetic models, and pharmacological innovation exemplifies the power of integrative approaches to tackle the complexity of tumor biology. As NNMT inhibitors move toward clinical translation, they hold the promise of reshaping not only how we target cancer-associated fibroblasts but also how we harness the immune system to eradicate tumors.
In conclusion, the discovery of NNMT’s role in CAF-mediated immunosuppression and its druggable nature marks a paradigm shift in the pursuit of effective cancer treatments. This pioneering work exemplifies how targeting the tumor stroma and its metabolic pathways can revive antitumor immunity and improve therapeutic outcomes. With ongoing developments anticipated in clinical trials, NNMT inhibitors represent a beacon of hope for overcoming immune evasion and achieving durable cancer remission.
Subject of Research: Cancer-associated fibroblasts, nicotinamide N-methyltransferase (NNMT), tumor immunosuppression, epigenetics, tumor microenvironment, cancer immunotherapy
Article Title: NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity.
Article References:
Heide, J., Bilecz, A.J., Patnaik, S. et al. NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity.
Nature (2025). https://doi.org/10.1038/s41586-025-09303-5
Image Credits: AI Generated
